Our studies over the past two decades have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result of our studies, the importance of Fc-Fc?R mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. While these strategies have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses that will effectively eliminate recurrences and thus result in long-term survival. This current proposal aims to mechanistically investigate general strategies to accomplish this goal by focusing on 1) inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), 2) define the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and 3) explore how the tumor microenvironment may be manipulated in order to augment these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-Fc?R interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can augment these pathways to result in long-term memory responses.